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MOCECULAR MECHANISMS OF HEPATOCYTOTOXICITY IN AUTOIMMUNE LIVER DISEASES

自身免疫性肝病肝细胞毒性的分子机制

基本信息

批准号：
09670576
负责人：
ZENIYA Mikio
金额：
$ 1.73万
依托单位：
The JIKEI University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

In order to clarify the molecular mechanisms of hepatotoxicity in autoimmune liver disease, we analysed the cytokine balance of autoimmune hepatitis (AIH) and primary billiary cirrhosis (PBC) by using newly developed intrecellular cytokine detection technique. The level of Th1 cytokine such as IFN-gamma in the active phase of AIH was high and IFN-gamma seemed to participate in the pathogenesis of active phase of AIH.Interestingly, it became clear that the level of IFN-gamma decreased during steroid therapy. On the contrary, the level of IL-10 increased during steroid therapy. These results indicated that Th1 dominancy was one of the particular charactor of AIH.We also analysed the TCR reperatoire of liver infiltrating lymphocyte (LIL) in AIH before and after steroid therapy to clarify the unique TCR V beta subfamily which may participate in the pathogenesis of AIH at active phase. Although there was no particular TCR V beta subfamily which was commonly used by LIL in AIH at active phase, unique amino acid was detected at N-D-N resion of CDR3 resion of V beta 7 which was shared by LIL of two HLA A24-DR4 positive patients. Interestingly, V beta 7 subfamily was disapeared from LIL after steroid therapy. These results indicated the possibility that unique amino acid which was detected at N-D-N resion of CDR3 resion of V beta 7 recognize the disease specific autoantigen of AIH.For father study, we should make clear that whether LIL-T cell which use such unique V beta subfamily particpate in the pathogenesis of AIH by recognizing the autoantigen and by secreting Th1 cytokine such as IFN-gamma.

为了阐明自身免疫性肝病肝毒性的分子机制，我们应用新近发展的细胞内细胞因子检测技术分析了自身免疫性肝炎（AIH）和原发性胆汁性肝硬化（PBC）的细胞因子平衡。在AIH活动期，IFN-γ等Th 1细胞因子水平较高，IFN-γ可能参与了AIH活动期的发病过程，但在激素治疗过程中IFN-γ水平明显下降。相反，IL-10水平在类固醇治疗期间增加。本研究还分析了激素治疗前后AIH患者肝浸润淋巴细胞（LIL）TCR库的变化，以阐明其独特的TCR V β亚家族可能参与活动期AIH的发病。虽然活动期AIH患者的LIL中并没有特异性的TCR V β亚家族，但在两例HLA A24-DR 4阳性患者的LIL中，在V β 7的CDR 3区的N-D-N区发现了一个独特的氨基酸序列。有趣的是，激素治疗后，LIL中V β 7亚家族消失。这些结果提示，V β 7的CDR 3区N-D-N区存在识别自身免疫性肝炎疾病特异性自身抗原的可能性，进一步的研究需要明确使用这种独特的V β亚家族的LIL-T细胞是否通过识别自身抗原和分泌IFN-γ等Th 1细胞因子参与了自身免疫性肝炎的发病过程。